Benchmark of Industry Practices: Surface Cleanliness Monitoring
Surfaces in the healthcare industry pose different levels of risk to the process based on the level of contact with the drug product. The types of surface are typically classified as direct, indirect, and non-product contact surfaces. Surface cleanliness monitoring must be adapted based on the potential risk to contaminate the next product. Therefore, the types of surfaces selected for monitoring should be scientifically justified. A walkthrough and observation of the surfaces to analyze potential exposure to the drug product is critical to support the justification.
The definition of the surface's type may differ between manufacturers. Therefore, this articles uses following descriptions:
- Direct product contact surface: a surface (e.g., equipment, material, items, etc.) that would be in direct contact with the product or any intermediate (e.g., media, buffer, etc.) that would enter in the final product composition.
- Indirect product contact surface: a surface (e.g., stopper bowl, scissors, etc.) that directly contacts a product contact surface and can transfer residues to the next product.
- Non-product contact surface: a surface (e.g., floor, ceiling, the exterior of equipment, etc.) that would never be in contact with the product or indirect or direct product contact surfaces.
Regulatory guidelines are comprehensive regarding cleaning monitoring requirements for direct product contact surfaces1-9. For nonproduct contact surfaces, the regulatory requirements and guidance are typically geared towards preventing contamination of the clean rooms environment10-14. For indirect product contact surfaces, however, the requirements regarding cleaning validation monitoring are not well developed5. Therefore, this article aims to share the practices performed by several European (bio)pharmaceutical manufacturers. Also, the article goal is to clarify the monitoring approach that should set up for indirect product contact surfaces. Finally, the article only focuses on process cleaning validation and monitoring of direct and indirect product contact surfaces.
A survey on several types of pharmaceutical manufacturers was performed. The goal of the survey is to understand how indirect product contact surfaces are monitored. 35 European manufacturers completed the survey; 57% non-sterile (e.g., tablet, liquid, and combined product), 23% sterile (e.g., biotechnology, liquid, and tablet product), 11% vaccine, 3% medical device, 6% hospital (e.g., early clinical production). The survey discussed routine monitoring alone and not control used during the initial validation, requalification, or revalidation. Based on the results of the survey, 86% of the manufacturers use different monitoring requirements based on the surface type, while, 14% use the same cleanliness requirements for both direct and indirect product contact surfaces (Figure 1).
Figure 1: 86% of the manufacturers have different monitoring requirements for direct and indirect product contact surfaces.
The surface type should be determined through a risk analysis where the product's risk of contamination (e.g., product residue or non-product residue) is assessed. The risk-based assessment should be coupled with a walkthrough and visualization of the production stream to confirm the type of surfaces.
12/13 October 2021
Live Online Training: GMP for Beginners in Sterile Manufacturing
The survey result showed that only 37% of manufacturers performed a risk-based analysis, coupled with walkthrough and visualization of the production stream, to confirm the surface type. However, 63% determine the surface type based only on experience and visualization of the different surfaces.
It is common sense to have different monitoring requirements for a direct and indirect product contact surface. The level of monitoring should be defined based on the risk of altering the product or eventually effecting the patient safety. A visual inspection for a non-product contact surface is enough. However, more stringent monitoring for direct product contact surfaces should be implemented (1-9). Finally, for indirect product contact surfaces, the monitoring strategy approach should be based on the potential risk to contaminate the product or a direct product contact surface, which is a common practice in the industry. However, from 30 of the manufacturers (Figure 1) that have different requirements for direct and indirect product contact surfaces, 50% of them adapt their monitoring strategy based on the criticality of the indirect contact product surfaces (Figure 2).
Note that answers:
- "Visual inspection and microbial removal and residue removal" or "Visual inspection and residue removal using the non-specific and specific method" may be considered the same monitoring approach for a direct contact product surface.
- Only one answer could be selected
Figure 2: 50% of the interviewed manufacturers that answered "no" in Figure 1 are adapting the monitoring of indirect product contact surfaces based on their criticality.
The monitoring approach for an indirect product contact surface may differ depending on the criticality of the surface and the position from the product or the process stream. Therefore, it is possible to define different types of indirect product contact surfaces based on their criticality. Only 54% of the manufacturers surveyed define different types of indirect contact surface (Figure 3).
Figure 3: 54% of the interviewed manufacturers have defined different types of indirect product contact surfaces.
The types of indirect product contact surface may be defined as follows: a. High risk indirect product contact surface: a surface that would be in contact with a direct product contact surface that is cleaned and/or sterilized. The indirect contact product contact surface may be in contact with the product residue during use; e.g., stopper bowl, spatula, and delivery chute in an isolator or RABS (Restricted Access Barrier System), lyophilizer (if considered as an indirect contact product surface). b. Low-risk indirect product contact surface: a surface that would be in contact with a direct product contact surface that is not cleaned and/or not sterilized. The indirect product contact surface is not in contact with the product residue; e.g., scissors cutting an unused and uncleaned hose. Therefore, depending on the criticality of the indirect product contact surface and the level of cleanness of the direct product contact surface, different monitoring approaches may be justified, as proposed in the decision tree (Figure 4).
* Depending on where in the process stream the surface is identified, the cleaning limit may vary.
** Endotoxin testing is generally performed for a sterile surface.
*** the frequency of routine monitoring should be scientifically, and risk-based justified.
Figure 4: an example of a decision tree for indirect product contact surface monitoring.
A walkthrough of the production stream and a visualization of the surface is not always sufficient. Therefore, the equipment usage and cleaning "lifecycle" should be analyzed to confirm the surface type and monitoring methods. For example, the external surface of a mobile vessel may be considered as a non-contact product surface. However, if this vessel is introduced into a washing machine, where both direct and indirect contact surfaces are also cleaned, specific monitoring should be set to confirm the absence of contamination (such as marker ink, adhesive present on the ticket) of a direct or indirect contact surface.
Case study #1: A multiproduct large sterile manufacturer disinfects their Restricted Access Barrier (RABS) after the filling of the batches in syringes is over. The disinfection procedure requests the operator to disinfect the RABS surface (indirect and non-direct contact product). The operator would disinfect the surface using a wet wipe containing the sporicidal agent. During a US FDA inspection, the regulator raised the following observation: "cleaning validations have not been performed for the following Equipment: The manual cleaning for the stopper bowl within filling line has not been validated."
The manufacturer answered to the observation by implementing a manual cleaning of the stopper bowl using visual inspection, and during validation, the bioburden limit and endotoxin testing were performed (case 4 of Figure 4). Finally, after cleaning, a disinfection using a sporicidal agent is performed and then rinsed.
Case study # 2: A multiproduct injectable drug manufacturing facility is using pliers and scissors to cut the hoses used to move bioburden control intermediate product from one vessel to another. The clean hoses are cut at a defined length based on the process need. Then, the hoses are sterilized prior to be used.
After the use of the pliers and scissors, the material is only disinfected using alcohol. After being disinfected, the material were sitting in the cleanroom without being adequately protected from the environment. During an audit lead by a European Medicine Agency representative, the following observation was raised: "the small equipment such as pliers, scissors are only disinfected using alcohol without cleaning before use of the small equipment."
The manufacturer addressed to the observation by implementing a manual cleaning of the material. This is followed by wrapping the material to protect them from the environment before re-use (Case 3 of Figure 4). In this case, during the cleaning validation, microbial monitoring after cleaning of the materials was not performed as the risk of microbial contamination was not identified.
14/15 October 2021
Live Online Training: Process Simulation / Media Fills
ConclusionThe level of monitoring of an indirect product contact surface after a cleaning process may depend on the criticality of the surface. The criticality is based on the potential risk to contaminate a product or a direct contact surface. Also, the criticality would vary depending on where the indirect product contact surface is positioned in the production stream. Therefore, the criticality of an indirect product contact surface should be determined using scientific justification, coupled with a visual inspection of surfaces before batch and cleaning processing. Different monitoring and limit approaches for indirect product contact surfaces are acceptable depending on their criticality. The frequency of monitoring should be scientifically justified, providing insight into why different approaches are being used at different manufacturer sites.
Author note: Walid El Azab wishes to sincerely thanks every person, colleague, and friend who participated in the survey.
Walid El Azab
... is "Senior Manager, Technical Services" at STERIS Life Science. He offers technical support for cleaning agents, desinfectants and products für sterility assurance and their application and validation. Walid is Secretary of the Belgium Qualified Person Association.
1 21 CFR 211.67: Equipment cleaning and maintenance
2 US Food and Drug Administration. Guide to inspections of validation of cleaning processes. Rockville, MD; 1993 July.
3 European Commission, Enterprise Directorate General. EudraLex, vol.4, Medicinal products for human and veterinary use: Good manufacturing practice. Office for Official Publications of
the European Communities: 2015.
4 Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme. Validation master plan installation and operational qualification: Non-sterile process validation.
Cleaning validation. Geneva, Switzerland; 2004 July.
5 European Medicines Agency, Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure
limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012), EMA/CHMP/CVMP/SWP/246844/2018,
6 Canada Health Products and Food Branch Inspectorate. Guidance Document. Cleaning validation guidelines: Drug and health products. Health Canada: Ottawa, Canada; 2002 Spring.
7 International Conference on Harmonization. Q7, Good manufacturing practice guide for active pharmaceutical ingredients. Geneva, Switzerland; 2000 Nov.
8 World Health Organization. Supplementary guidelines on good manufacturing practices: Validation. Geneva, Switzerland; 2005
9 US Food and Drug Administration. Guidance for industry. Current good manufacturing practice for finished pharmaceuticals. Rockville, MD; 2006 Apr.
10 European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1, Manufacture of Sterile Medicinal Products, 2009.
11 United States Department of Health and Human Services Food and Drug Administration, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good
Manufacturing Practice, 2004.
12 Regulatory Science of Pharmaceuticals and Medical Devices from Ministry of Health, Labour and Welfare of Japan, Guidance on the Manufacture of Sterile Pharmaceutical Products by
Aseptic Processing, 2006.
13 European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 3, Premises and equipment, 2015.
14 European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 5, Production, 2015.